Investigating Ultrastructural Collagen Changes in Osteogenesis Imperfecta

研究成骨不全症中胶原蛋白的超微结构变化

• 批准号: 7541057
• 负责人: Joseph Michael Wallace
• 金额: $ 4.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541057
• 关键词: Affect; American; Architecture; Atomic Force Microscopy; Binding; Biochemistry; Biological; Biological Models; Biomedical Engineering; Bone Diseases; Bone Matrix; Bone Tissue; Carbon; Cells; Charge; Chemicals; Clinical; Collagen; Collagen Fibril; Collagen Type I; Communities; Competence; Connective Tissue; Coupled; Data; Dendrimers; Dentin; Development; Disease; Doctor of Philosophy; Drug or chemical Tissue Distribution; Engineering; Environment; Excision; Fracture; Funding; Goals; Hereditary Disease; Human; Image; In Situ; In Vitro; Investigation; Joints; Knock-in Mouse; Knowledge; Length; Life; Link; Literature; Measures; Mechanics; Methods; Michigan; Mission; Modeling; Modification; Monitor; Morphology; Mus; Mutation; Nature; Organism; Osteogenesis Imperfecta; Patients; Personal Satisfaction; Physiology; Polymers; Predisposition; Preparation; Property; Protein Binding; Proteins; Public Health; Range; Research; Research Design; Research Infrastructure; Sampling; Series; Severities; Skeletal system; Skeleton; Solid; Structure; Surface; Tail; Tendon structure; Testing; Tissues; Translating; Trauma; Treatment Protocols; United States; Universities; Width; Wild Type Mouse; Work; base; bone; bone quality; burden of illness; density; design; disability; human study; innovation; insight; interdisciplinary approach; mineralization; physical property; research study; size

DESCRIPTION (provided by applicant): The lack of understanding of how altered collagen structure in Osteogenesis Imperfecta (Ol) translates to insufficiencies in tissue integrity is a critical impediment to the implementation of treatment protocols designed to return bone properties to normal levels. The long-term goal is to understand how alterations in the bone ultrastructure in Ol influence higher level properties. The overall objective of this proposal is to relate [morphological changes] in Type I collagen fibrils from connective tissues of Ol mice [to fibril mechanical integrity and] the altered ability of proteins to bind to this collagen as measures of functional competence. The central hypothesis is that alterations in the [width, axial spacing and packing] of Ol Type I collagen fibrils will result in inappropriate organic matrix organization, [decreased fibril modulus] and [improper protein binding to diseased fibril] surfaces. The rationale for the proposed research is that once mechanical differences in Ol [tissues] can be linked to explicit changes in Type I collagen, appropriate treatment options can be developed to specifically target altered collagen functions. Therefore, this research is relevant to the NIH's mission to apply fundamental knowledge about the nature of living systems to extending healthy human life and reducing the burdens of illness and disability. Based on strong preliminary data and a solid literature base, the central hypothesis will be tested by pursuing two specific aims: 1) Identify morphological and organizational consequences of Ol in Type I collagen; and 2) Establish changes [in mechanical integrity and] in the ability of proteins to bind to Type I collagen in Ol as measures of functional competence. Atomic force microscopy coupled with dendritic polymers as model proteins will be used to probe the collagen of wild type, [Brtl/+] and [Brtl/Brtl] mice representing a [range] of Ol severity. Under the first aim, Type I collagen will be imaged in a variety of biological settings to determine how collagen physically [changes with mutation severity]. Under the second aim, physical differences in collagen will be correlated [with fibril modulus and] with alterations in the ability of proteins to bind to fibril surfaces as measures of functionality. The approach is innovative because it will begin linking architectural and functional aspects of Type I collagen at the ultrastructural level to higher-level properties in situ. As the United States is part of the current worldwide Bone and Joint Decade initiative, this research has clear relevance to public health. Uncovering the link between bone quality and structural integrity remains a key goal of the bone research community. Therefore, this research is not only applicable to Ol patients, but has broader implications for investigating other diseases related to ultrastructural modifications of bone.

描述（由申请人提供）：缺乏对成骨不全症（Ol）中胶原结构改变如何转化为组织完整性不足的理解，是实施旨在将骨特性恢复到正常水平的治疗方案的关键障碍。长期目标是了解Ol中骨超微结构的改变如何影响更高水平的特性。本提案的总体目标是将来自Ol小鼠结缔组织的I型胶原原纤维的[形态学变化]与纤维的机械完整性和]蛋白质与胶原蛋白结合能力的改变联系起来，作为功能能力的衡量标准。核心假设是，Ol型I型胶原原纤维的[宽度、轴向间距和排列]的改变将导致不适当的有机基质组织，[纤维模量降低]和[与患病纤维的蛋白质结合不当]表面。这项研究的基本原理是，一旦Ol[组织]的机械差异可以与I型胶原蛋白的明显变化联系起来，就可以开发出适当的治疗方案，专门针对改变的胶原蛋白功能。因此，这项研究与NIH的使命有关，即应用有关生命系统本质的基本知识来延长健康的人类生命，减少疾病和残疾的负担。基于强大的初步数据和坚实的文献基础，中心假设将通过追求两个特定目标来验证：1)确定I型胶原中Ol的形态学和组织后果；2)建立[机械完整性和]蛋白质与I型胶原蛋白结合能力的变化，作为功能能力的衡量标准。原子力显微镜结合树突聚合物作为模型蛋白，将用于探测野生型，[Brtl/+]和[Brtl/Brtl]小鼠的胶原蛋白，代表Ol严重程度的[范围]。在第一个目标下，I型胶原蛋白将在各种生物环境下成像，以确定胶原蛋白的物理变化[随着突变严重程度的变化]。在第二个目标下，胶原蛋白的物理差异将[与原纤维模量和]与蛋白质与原纤维表面结合能力的变化相关，作为功能的衡量标准。这种方法是创新的，因为它将开始在超微结构水平上将I型胶原蛋白的结构和功能方面与原位的更高水平特性联系起来。由于美国是目前全球骨与关节十年倡议的一部分，这项研究与公众健康明显相关。揭示骨质量和结构完整性之间的联系仍然是骨研究界的一个关键目标。因此，本研究不仅适用于Ol患者，而且对研究其他与骨超微结构改变相关的疾病具有更广泛的意义。